Pharmaceutical preparation for percutaneous treatment of local edemas employing acetazolamide

ABSTRACT

Method for percutaneous treatment of edemas of humans to reduce their swelling, by percutaneous application of a pharmaceutical preparation comprising an active element consisting of acetazolamide in a concentration of between 1 to 50% incorporated in a vehicle which is compatible with percutaneous administration.

CROSS REFERENCE

This is a continuation-in-part application with respect to our copendingUnited States Patent Application 146,298 filed May 24, 1971, now U.S.Pat. No. 3,934,016.

BACKGROUND OF THE INVENTION

The present invention relates to an improvement in therapeutic meansemployed for treatment of localized edemas of humans. More particularlythe invention concerns percutaneous use of acetazolamide and theadvantages inherent in this manner of introducing the acetazolamide. Itis generally recognized that use of a diuretic by mouth for treatment oflocalized edemas presents metabolic drawbacks such as modification ofionic equilibrium, without contributing any very definitive curativeeffect on the edema.

In the case of acetazolamide, oral administration causes substantialacidosis (determined by the decrease in the value of the alkalinereserve of the blood) as well as a loss of potassium (detected by thedrop of the potassium content of the serum). A good improvement in thetreatment would consist in increasing local therapeutic effects ofacetazolamide on edemas and decreasing the harmful effects (acidosis andhyperkalemia).

BRIEF DESCRIPTION OF THE INVENTION

Applicants have found now that by administering acetazolamidepercutaneously in the form of an ointment or cream one can reducelocalized edemas without repercussion on blood constants.

1. First of all, it was discovered that acetazolamide, contrary to otherdiuretic molecules, has the property of passing through the epidermalbarrier. This property can be shown by the following experiment (fromLipschitz et al., J. Pharm. Exp. Therap. 1943, 79, p. 97). Rats, dividedinto 3 homogeneous lots, were given an aqueous overload of 5% of theirbody weight by intraperitoneal injection of physiological salt solution.One control lot received merely an application of the vehicle of theointment. A series of lots (rats) was treated by application of ointmentcontaining 10% acetazolamide. A series of lots was treated by oraladministration of acetazolamide.

    ______________________________________                                                      % increase in                                                                 diuresis at the                                                 Series        end of 4 hr. Probability                                        ______________________________________                                        Acetazolamide per                                                             os in a dose of:                                                              2 mg/kg         22%        0.02 < p < 0.05                                    5 mg/kg         33%        p < 0.001                                          10 mg/kg        35%        p < 0.001                                          20 mg/kg        48%        p < 0.001                                          Acetazolamide in                                                              ointment in a dose of: -10 mg/kg                                                              20%        not significant                                    20 mg/kg        33%        0.01 < p < 0.02                                    100 mg/kg       42%        p < 0.001                                          ______________________________________                                    

The same experiment, carried out by administering other diureticproducts such as triamterene, spironolactone, mercaptomerine,theophylline, in ointment form, showed that these substances did notcause diuresis.

2. In the second step, it was sought to determine whether acetazolamideadministered as an ointment could inhibit formation of a localized edemacaused in an animal and in what dose. A method was used in which anedema of the paw of the rat was caused by injection of kaolin into theplantar aponeurosis. (Method of J. Millebrecht - Arzneimittel Forschung1954, 4, 607). It was found that acetazolamide significantly opposesformation of edema, first, starting with a dose of 10 mg/kg in ointmentform and second, starting with a dose of 50 mg/kg per os.

3. Thereupon the doses causing diuresis or a protective effect withrespect to edema, in accordance with the two methods of administration,were compared. The following table is obtained:

    ______________________________________                                                   Dose in mg/kg as from which there                                  Method of  is significantly observed:                                         administration                                                                           A diuretic effect                                                                            An anti-edema effect                                ______________________________________                                        Per os      2             50                                                  Percutaneous                                                                             20             10                                                  ______________________________________                                    

This table makes it possible to note that administration ofacetazolamide, percutaneously, makes it possible to obtain antiedemaeffects in low dose, far before the diuretic effect.

4. It was then verified clinically that administration of acetazolamidein an ointment actually provided a suitable therapeutic effect withoutcausing harmful secondary effects. For this purpose, two classes ofpatients having localized edemas were selected, namely:

a. Post-traumatic edemas,

b. Edemas of cellulitic type.

The acetazolamide was administered in the form of a 10% ointment and theresults were classified as:

Very good: the measurements had become normal again, the pain haddisappeared, perfect mobility of the joints.

Good: Persistence of a certain degree of edema not having any functionalconsequence, almost complete disappearance of pain.

Rather good: presence of a partial improvement of the edema with slightfunctional disturbance, attenuation of the pain with persistence ofmoderate disturbance.

Zero: failure or insufficient action leaving appreciable functionaldisturbance, inadequacy or absence of effect on the pain.

    __________________________________________________________________________                    Very    Rather  % Very Good                                               Total                                                                             Good                                                                              Good                                                                              Good                                                                              Zero                                                                              + Good                                        __________________________________________________________________________    Post-traumatic edemas                                                                     78  45  15   9   9  78                                            Cellulitic edemas                                                                         92  25  39  12  16  70                                            __________________________________________________________________________

The effects on the alkaline reserve and on the blood potassium weredetermined:

Alkaline reserve: 56 observations, all within normal values.

Ionogram: 30 observations, all within normal values.

5. It was verified clinically that administration of acetazolamide in anointment gives therapeutic effects superior to administration by mouth.For this purpose, acetazolamide was administered in succession by one orthe other method:

in a first group of patients: 8 days by mouth and then 8 days locally,

in a second group: 8 days locally and then 8 days by mouth.

This procedure is necessary in order to eliminate the spontaneousimprovement of the edema which favors in particular the first formadministered. The results were as follows:

    ______________________________________                                        Average decrease                                                              of edema       Tablets  Ointment Probability                                  ______________________________________                                        Tablets before ointment                                                                      0.68     0.77     10 < p < 50                                                 Ointment Tablets                                               Ointment before tablets                                                                      1.81     0.63     1 < p < 2                                    ______________________________________                                         Therefore, the administration of ointment proves to be more effective than     the administration of tablets, with the probability of 98 to 99%.

The present invention can be carried out by conventional methods, theacetazolamide being incorporated in vehicles compatible withpercutaneous administration. Thus it can be presented in the form of asuspension or emulsion, leading to conventional presentations, such aslotions, milks, creams, ointments, etc. The acetazolamide concentrationwill be between 1 and 50% and will advantageously be established at 10%.

EXAMPLES

The following examples are given to permit a better understanding of theinvention, without, however, limiting its scope:

    ______________________________________                                        1.      Anhydrous ointment                                                             Formula                                                              acetazolamide             10                                                  poly-oxy-ethylene glycol 1500                                                                           75                                                  poly-oxy-ethylene glycol 300                                                                            15                                                  ______________________________________                                    

In a double-jacketed stainless steel vessel, melt the mixture ofpoly-oxy-ethylene glycols at 48° C. Slowly add the acetazolamide in veryfinely pulverized form, with agitation. Cool with agitation to about 20°C and distribute in suitable containers.

    ______________________________________                                        2.      Skin Cream                                                                     Formula                                                              acetazolamide             10                                                  poly-oxy-ethylene glycerides                                                                            10                                                  polyethylene glycol stearate 300                                                                        10                                                  preservatives                                                                 methyl para-hydroxybenzoate                                                                             0.07                                                propyl para-hydroxybenzoate                                                                             0.03                                                water q.s.p.              100 g                                               ______________________________________                                    

In a stainless steel vessel, melt the mixture of poly-oxy-ethyleneglycerides and polyethylene glycol stearate 300 at 38° C. Thepreservative, which is an anti-fungus and anti-microbic agent, may inparticular be a mixture of methyl para-hydroxybenzoate and propylparahydroxybenzoate. Add the finely pulverized acetazolamide. Stir untilcompletely dispersed. Slowly add an aqueous solution of thepreservative, brought to 38° C. Stir until homogeneous. Cool slowly to20° C with agitation. Distribute into suitable receptacles.

    ______________________________________                                        3.      Suspension for Use on the Skin                                                 Formula                                                              acetazolamide             10                                                  polyethylene glycol stearate 300                                                                        10                                                  stearic acid               5                                                  petrolatum oil             3.5                                                ascorbyl palmitate         3                                                  water q.s.p.              100 g                                               ______________________________________                                    

In a stainless steel vessel, melt at 40° C the mixture of polyethyleneglycol stearate 300, stearic acid and oil of petrolatum. Add the finelypulverized acetazolamide. Stir until completely dispersed. Slowly addanaqueous solution of the preservative, brought to 38° C. Thepreservative may in particular be ascorbyl palmitate. Stir untilhomogeneous. Cool slowly to 20° C with agitation. Distribute intosuitable receptacles.

We claim:
 1. A pharmaceutical composition for local external cutaneoustreatment of a local subcutaneous edema of a human, the compositioncomprising a suspension for skin use consisting of the following:10parts of acetazolamide (5-acetamido-1,3,4-thiadiazole-2-sulfonamide), 10parts of polyethylene glycol 300, 5 parts of stearic acid, 3.5 parts ofliquid petrolatum, 3 parts of ascorbyl palmitate and 100 parts of waterq.s.p.
 2. A skin cream for local external cutaneous treatment of a localsubcutaneous edema of a human, the skin cream comprising:10 parts ofacetazolamide (5-acetamido-1,3,4-thiadiazole-2-sulfonamide), 10 parts ofpoly-oxy-ethylene glycerides, 10 parts of polyethylene glycol stearate300, 0.07 parts of methyl para-hydroxybenzoate, 0.04 parts of propylpara-hydroxybenzoate and 100 parts of water q.s.p.
 3. A method forcutaneous local treatment of a local subcutaneous edema of a human whichmethod comprises applying to the skin over the edema a pharmaceuticalcomposition which comprises:a pharmaceutical carrier compatible withcutaneous external application, a diuretic agent capable of passing theepidermal barrier incorporated in the pharmaceutical carrier; said agentbeing acetazolamide (5-acetamido-1,3,4-thiadiazole -2-sulfonamide), witha range of concentration being between 1% and 50% by weight.
 4. A methodfor cutaneous local treatment of a local subcutaneous edema of a humanwhich method comprises applying to the skin over the edema apharmaceutical composition which comprises:an emulsified pharmaceuticalcarrier compatible with cutaneous external application, a diuretic agentcapable of passing the epidermal barrier incorporated in thepharmaceutical carrier; said agent being acetazolamide(5-acetamido-1,3,4,-thiadiazole-2-sulfonamide), with a range ofconcentration being between 1 and 50% by weight.